Effects of Abscisic Acid on Insulin Sensitivity Biotherapeutics Inc (BTI), a spinoff Company of Virginia Tech, is developing innovative products for personalized nutrition. BTI has licensed 11 patent applications from Virginia Tech related to new methods of lowering blood sugar levels and suppressing inflammation during prediabetes and type 2 diabetes, including significant intellectual properties (IP) on the anti-diabetic actions of abscisic acid (ABA). We developed an ABA extract from figs (ABAlifeTM) and established ABA as a Generally Regarded as Safe (GRAS) ingredient. Significance & Product: Prediabetes afflicts 86 million Americans and has recently risen to more than 3 million new cases per year in the U.S. alone. A prediabetic person is likely to become diabetic within 10 years, because many people with prediabetes have no symptoms and do not adhere to lifestyle and diet changes or medical treatment. According to the CDC, 9 out of 10 Americans with prediabetes don?t know they have it. Dietary ABA supplementation is a safe and non-toxic method to improve glycemic control in mice, rats, and humans with an effective dose as low as 1 g/kg and no side effects. The goal of this Fast-Track proposal is to develop ABA as a medical food ingredient for glycemic control. The Specific Aims for the SBIR Fast-Track Phase I application are to: AIM 1. Validate the mechanisms of action and cell specificity of dietary ABA in skeletal muscle of mice. We will investigate differential ABA-induced LANCL2 signaling in skeletal muscle cells during diabetes. We will employ LANCL2 conditional knockout animals to address ABA?s cell-specific effects. AIM 2. Characterize the potential for translation of LANCL2-dependent mechanism in human primary skeletal muscle cells. Under ABA or vehicle treated conditions, with or without siRNA/CRISP LANCL2, we will assess GLUT4 translocation, glucose uptake and oxidation, and glycogen synthesis. Transition Milestones are: ABA is dependent on muscle-specific expression of LANCL2 and ABA induces increases in the uptake and metabolism of glucose in mice and ex vivo culture of primary human muscle cells. The Specific Aims for the SBIR Fast-Track Phase II application are to: AIM 3. Perform a 14-day human clinical study in prediabetic subjects to assess the effects of ABA on glucose homeostasis and tolerability. Using a two group, randomized, placebo controlled crossover trial, we will evaluate how ABA (95 ?g) twice daily effects insulin sensitivity within skeletal muscle by the hyperinsuliemic, euglycemic clamp, combined with percutaneous muscle biopsies to directly interrogate LANCL2 activation and GLUT4 translocation in enhanced insulin sensitivty. Commercial Application: BTI will have generated claims for ABA in maintaining healthy glucose levels. ABA products could disrupt the $9B medical food, 15B functional water, and $58B diabetes markets by 2018.